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- Osinski, V., et al.
(author)
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In vivo liposomal delivery of PPAR alpha/gamma dual agonist tesaglitazar in a model of obesity enriches macrophage targeting and limits liver and kidney drug effects
- 2020
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In: Theranostics. - : Ivyspring International Publisher. - 1838-7640. ; 10:2, s. 585-601
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Journal article (peer-reviewed)abstract
- Macrophages are important regulators of obesity-associated inflammation and PPAR alpha and -gamma agonism in macrophages has anti-inflammatory effects. In this study, we tested the efficacy with which liposomal delivery could target the PPAR alpha/gamma dual agonist tesaglitazar to macrophages while reducing drug action in common sites of drug toxicity: the liver and kidney, and whether tesaglitazar had anti-inflammatory effects in an in vivo model of obesity-associated dysmetabolism. Methods: Male leptin-deficient (ob/ob) mice were administered tesaglitazar or vehicle for one week in a standard oral formulation or encapsulated in liposomes. Following the end of treatment, circulating metabolic parameters were measured and pro-inflammatory adipose tissue macrophage populations were quantified by flow cytometry. Cellular uptake of liposomes in tissues was assessed using immunofluorescence and a broad panel of cell subset markers by flow cytometry. Finally, PPAR alpha/gamma gene target expression levels in the liver, kidney, and sorted macrophages were quantified to determine levels of drug targeting to and drug action in these tissues and cells. Results: Administration of a standard oral formulation of tesaglitazar effectively treated symptoms of obesity-associated dysmetabolism and reduced the number of pro-inflammatory adipose tissue macrophages. Macrophages are the major cell type that took up liposomes with many other immune and stromal cell types taking up liposomes to a lesser extent. Liposome delivery of tesaglitazar did not have effects on inflammatory macrophages nor did it improve metabolic parameters to the extent of a standard oral formulation. Liposomal delivery did, however, attenuate effects on liver weight and liver and kidney expression of PPAR alpha and -gamma gene targets compared to oral delivery. Conclusions: These findings reveal for the first time that tesaglitazar has anti-inflammatory effects on adipose tissue macrophage populations in vivo. These data also suggest that while nanoparticle delivery reduced off-target effects, yet the lack of tesaglitazar actions in non-targeted cells such (as hepatocytes and adipocytes) and the uptake of drug-loaded liposomes in many other cell types, albeit to a lesser extent, may have impacted overall therapeutic efficacy. This fulsome analysis of cellular uptake of tesaglitazar-loaded liposomes provides important lessons for future studies of liposome drug delivery.
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2. |
- Baum, Sebastian, et al.
(author)
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Detecting solar chameleons through radiation pressure
- 2014
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In: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 739, s. 167-173
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Journal article (peer-reviewed)abstract
- Light scalar fields can drive the accelerated expansion of the universe. Hence, they are obvious dark energy candidates. To make such models compatible with tests of General Relativity in the solar system and "fifth force" searches on Earth, one needs to screen them. One possibility is the so-called "chameleon" mechanism, which renders an effective mass depending on the local matter density. If chameleon particles exist, they can be produced in the sun and detected on Earthexploiting the equivalent of a radiation pressure. Since their effective mass scales with the local matter density, chameleons can be reflected by a dense medium if their effective mass becomes greater than their total energy. Thus, under appropriate conditions, a flux of solar chameleons may be sensed by detecting the total instantaneous momentum transferred to a suitable opto-mechanical force/pressure sensor. We calculate the solar chameleon spectrum and the reach in the chameleon parameter space of an experiment using the preliminary results from a force/pressure sensor, currently under development at INFN Trieste, to be mounted in the focal plane of one of the X-Ray telescopes of the CAST experiment at CERN. We show, that such an experiment signifies a pioneering effort probing uncharted chameleon parameter space.
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